KR20060021896A - Indole derivatives in the form of serotonin reuptake inhibitors - Google Patents

Abstract

The present invention provides for the preparation of drugs for the treatment of diseases associated with serotonin receptors and / or serotonin reuptake, in particular for the manufacture of drugs such as anxiolytics, antidepressants, neuroleptics and / or antihypertensives and / or obsessive compulsive disorders. , Compounds of formula (I) used to favor sleep disorders, delayed dyskinesia, learning disorders, senile memory loss, eating disorders such as bulimia, and / or irritable bowel syndrome and / or sexual dysfunction.

Description

Indole derivatives in the form of serotonin reuptake inhibitors {INDOLE DERIVATIVE IN THE FORM OF SEROTONIN REABSORBING INHIBITORS}

The present invention provides a novel indole derivative, a method for preparing the same, and a preparation for the preparation of a medicament for the treatment and prophylaxis of diseases associated with serotonin reuptake and / or serotonin receptors (serotonin, 5-hydroxytrytamine, 5-HT). It relates to the use of the compound.

For example, the following forms of 5-HT receptors are known: 5-HT _1A , 5-HT _1B , 5-HT _1D , 5-HT _2A , 5-HT _2B , 5-HT _2C , 5-HT ₃ , 5 -HT ₄ , 5-HT ₆ , 5-HT ₇ . Subtypes have also been found that differ in tissue specificity, mode of action and also properties, for example 5-HT _{1D α} and 5-HT _{1D β} .

WO9951575 discloses indole derivatives that affect 5-HT _1A self-receptors and 5-HT transporters and are usable for the treatment of depression.

DE19514567 discloses a piperazinylbenzofuran acting on the central nervous system, and EP0655442 discloses a piperazine derivative having a tachykinin-antagonistic action.

Indole piperazine derivatives are known from EP0648767, US5532241, EP0407844, EP0376607, BE771285, GB1075156, GB118064, FR1551082 and EP 0 736 525. These compounds are effective serotonin reuptake inhibitors and 5-HT _1A receptor agonists.

WO9616056, WO9617842, WO9718202, WO9718203, WO9745432 and WO9719943 disclose indolepiperidine and indolepiperazine derivatives which are effective 5-HT _{1D α} receptor agonists. The compounds disclosed herein are used for the treatment of diseases associated with migraine due to their vasoconstrictive action.

The present invention aims to find novel compounds which can be used for the manufacture of a medicament.

The compounds of formula (I) according to the invention and their physiologically acceptable acid-addition salts have useful pharmacological properties and are well tolerated. Surprisingly, compounds of formula I according to the invention have been found to act on the central nervous system. They act as selective serotonin reuptake inhibitors, show serotonin-acting and -antagonistic properties, and thus affect serotonergic delivery. In particular, they show 5-HT _1A -acting action and have an affinity for serotonin receptor sub-form 5-HT ₄ .

Accordingly, the present invention relates to compounds of formula I:

(Wherein,

X is N or CH,

R ¹ , R ³ are independently of each other H, OH, OA, CN, Hal, COR ⁴ or CH ₂ R ⁴ ,

R ² is H, optionally mono- or poly-substituted by Hal, linear or branched alkyl having 1 to 6 carbon atoms, alkaryl, alkheteroaryl, or heteroaryl,

R ⁴ is OH, OA, NH ₂ , NHB or NB ₂ ,

A and B are each independently alkyl having 1 to 6 carbon atoms,

m is 2, 3, 4, 5 or 6,

n is 0, 1, 2, 3 or 4)

And physiologically acceptable salts, derivatives, solvates and stereoisomers thereof, and mixtures of all proportions thereof.

Hal is preferably F, Cl or Br is also I.

A and B are independently of each other, preferably unsubstituted and have 1, 2, 3, 4, 5 or 6 carbon atoms.

Alkyl having 1 to 6 carbon atoms is preferably methyl, ethyl, n-propyl, also preferably isopropyl, butyl, isobutyl, secondary-butyl or tert-butyl, also n-pentyl, neopentyl, iso Pentyl or n-hexyl.

Alkaryl is alkyl having 1 to 6 carbon atoms connected to an aromatic ring system containing 6 or 10 centers such as, for example, benzyl or phenethyl.

Alkheteroaryl is alkyl having 1 to 6 carbon atoms linked to an aromatic heterocycle containing 5, 6 or 10 centers such as, for example, pyridin-2-ylmethyl.

Heteroaryl is a monovalent monocyclic or bicyclic heterocycle having 5-12 ring atoms having one or more aromatic rings, wherein one, two or three ring atoms are selected from N, O or S. Heteroaryls are independently from each other, for example from alkyl, cycloalkyl, cycloalkylalkyl, Hal, NO, CN, alkoxy, NH ₂ , acylamino, monoalkylamino, dialkylamino, haloalkyl, haloalkoxy or heteroalkyl Optionally substituted with 1-4 substituents selected. Heteroaryls are, for example, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrroylyl, pyrazolyl, pyrazinyl, pyrimidinyl, benzofuranyl, Tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindoleyl, benzoxazolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, benzimida Zolyl, benzisoxazolyl, or benzothienyl, or derivatives thereof.

X is N,

R ¹ , R ³ are independently of each other CN, COR ⁴ or CH ₂ R ⁴ ,

R ² is linear or branched alkyl, alkaryl, alkheteroaryl or heteroaryl having 1 to 6 carbon atoms,

R ⁴ is OH, NH ₂ , NHB or NB ₂ ,

A and B are each independently alkyl having 1 to 6 carbon atoms,

m is 4,

a compound of formula (I) wherein n is 0,

And mixtures of physiologically acceptable salts, derivatives, solvates and stereoisomers thereof with all ratios thereof.

The following compounds:

a. 5- {4- [4- (5-cyano-1-ethyl-1H-indol-3-yl) butyl] piperazin-1-yl} benzo-furan-2-carboxamide

b. 5- {4- [4- (5-cyano-1-isopropyl-1H-indol-3-yl) butyl] piperazin-1-yl} benzofuran-2-carboxamide

c. 5- {4- [4- (1-benzyl-5-cyano-1H-indol-3-yl) butyl] piperazin-1-yl} benzofuran-2-carboxamide

d. 5- {4- [4- (5-cyano-1-propyl-1H-indol-3-yl) butyl] piperazin-1-yl} benzofuran-2-carboxamide

e. 5- {4- [4- (5-cyano-1-pyridin-2-ylmethyl-1H-indol-3-yl) butyl] piperazin-1-yl} benzofuran-2-carboxamide

f. 5- {4- [4- (5-cyano-1-phenethyl-1H-indol-3-yl) butyl] piperazin-1-yl} benzofuran-2-carboxamide

And particularly the compound 5- {4- [4- (5-cyano-1-methyl-1H-indol-3-yl) butyl] piperazin-1-yl} benzo-furan-2-carboxamide Do.

In addition, according to the invention, there are mixtures of all physiologically acceptable salts, derivatives, solvates and stereoisomers of these compounds with all proportions thereof.

The invention also relates to optically active forms (stereoisomers), enantiomers, racemates, diastereomers, and hydrates and solvates of such compounds.

Pharmaceutically or physiologically acceptable derivatives are for example taken to mean salts of the compounds according to the invention and also so-called prodrug compounds. Prodrug compounds are for example taken to mean compounds of the formula (I) which are modified with alkyl or acyl groups, sugars or oligopeptides and which are rapidly degraded or liberated in an organism to give the active compounds according to the invention. It also includes biodegradable polymer derivatives of the compounds according to the invention as described, for example, in Int. J. Pharm. 115 (1995), 61-67.

Suitable acid-addition salts are inorganic or organic salts of all physiologically or pharmacologically acceptable acids, for example halides, in particular hydrochlorides or hydrobromide, lactates, sulfates, citrates, tartrates, horses Latex, fumarate, oxalate, acetate, phosphate, methylsulfonate or p-toluenesulfonate.

Solvates of compounds of formula (I) are taken to mean adducts of inert solvent molecules for the compounds of formula (I) formed due to their mutual attraction. Solvates are, for example, hydrates such as monohydrates, dihydrates or alcoholates, ie addition compounds with alcohols (eg methanol or ethanol, etc.).

The invention also relates to a mixture of compounds of formula I according to the invention, for example 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: 1000 For example, a mixture of two diastereomers.

The present invention also provides

a) a compound of formula II:

(Wherein,

R ¹ and m have the meanings indicated above and Y is halogen, in particular chlorine or an alcohol provided with protecting groups known to those skilled in the art)

To the compound of formula III:

R ² -Z

(Wherein,

R ² has the meaning indicated above, Z is a leaving group known to those skilled in the art, for example p-tosyl, trifluoromethanesulfonyl, methanesulfonyl, benzenesulfonyl, Br, Cl or I); React,

b) a compound of formula IV obtained according to a):

Is a compound of Formula (V) or a salt thereof:

(Wherein,

R ³ , X and n have the meanings indicated above) and optionally add a base in the solvent to react at the boiling point of the solvent,

c) a process for the preparation of a compound of formula (I), characterized in that the base of the compound of formula (I) is converted to one of its salts by treatment with an acid.

In each case, the reaction may be carried out stepwise.

Starting compounds of formula (II), (III), (VI) and (V) are generally known. If these are novel, they can be produced by a method known per se.

If desired, the starting material may be formed in situ by not immediately separating it from the reaction mixture but instead immediately converting it to the compound of formula (I).

The starting material can be bound (melted) in the absence of solvent in a sealed reaction vessel or autoclave. However, it is also possible to react the starting material in the presence of an inert solvent.

Suitable inert solvents are, for example, heptane, hexane, petroleum ether, benzene, toluene, xylene, trichloroethylene-, 1,2-dichloroethanetetrachloromethane, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether (preferably for indole nitrogen substitution), tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); Nitriles such as acetonitrile; Esters such as ethyl acetate, carboxylic acids or acid anhydrides such as acetic acid or acetic anhydride, nitro compounds such as nitromethane or nitrobenzene, if necessary also mutual mixtures of these solvents or mixtures with water.

The reaction can also be carried out using a heterogeneous phase, preferably with an aqueous phase and a benzene or toluene phase. At this time, a phase-transfer catalyst such as for example tetrabutylammonium iodide, and optionally an acylation catalyst such as for example dimethylaminopyridine is used.

The amount of solvent is not critical but preferably adds from 10 g to 500 g of solvent per g of compound of formula (I) to be reacted.

Acid-binding agents, for example alkali or alkaline earth metal hydroxides, carbonates or bicarbonates, or other alkali or alkaline earth metal salts of weak acids, preferably potassium, sodium or calcium salts, or organic bases such as triethyl It may be advantageous to add an amine component such as amine, dimethylamine, pyridine or quinoline, or an excess of amine component.

Suitable reaction temperatures are 10 to 180 ° C, preferably 20 to 150 ° C and very particularly preferably 40 to 100 ° C.

The reaction is preferably carried out at temperatures of 1 to 200 bar and -80 ° C to + 150 ° C, particularly preferably at room temperature and atmospheric pressure. Preferably from 1.5 to 120 bar and in particular from 2 to 100 bar.

The reaction is preferably carried out at pH 6-10.

The reaction period depends on the reaction conditions chosen. Generally the reaction period is from 0.5 hours to 10 days, preferably from 1 to 24 hours. When using microwave, the reaction time can be reduced to 1 to 60 minutes.

Compounds of formula (I) and also starting materials for the preparation thereof are also described in the literature (for example, standard workbooks such as Houben-Weyl, Methoden der organischen Chemie, Georg-Tieme-Verlag, Stuttgart). By the known method, as described, it is known to the reaction and prepared under suitable reaction conditions. Modifications also known per se but not detailed in this specification can also be used.

Compounds of formula (II) can be obtained through conventional reaction-finishing steps, such as after removal of the solvent, for example by adding and extracting water to the reaction mixture. It may then be advantageous to carry out distillation or crystallization for further purification of the product.

The acid of formula (I) can be converted to the relevant addition salt using base by evaporating, for example, an equivalent amount of acid and base in an inert solvent such as ethanol. Particularly suitable bases for this reaction are those from which physiologically acceptable salts are obtained. Thus, the acid of formula (I) can be converted to the corresponding metal salts, in particular alkali metal or alkaline earth metal salts, or to the corresponding ammonium salts, using bases (eg sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate). Also suitable are organic bases from which physiologically acceptable salts, such as, for example, ethanolamine, are obtained.

On the other hand, the base of the formula (I) can be converted to the related acid-addition salt using the acid by, for example, reacting and then evaporating an equal amount of base and acid in an inert solvent such as ethanol. Suitable acids for this reaction are, in particular, acids which produce physiologically acceptable salts. Thus, for example, hydrofluoric acid such as sulfuric acid, nitric acid, hydrochloric acid or bromic acid, phosphoric acid such as orthophosphoric acid, inorganic acids such as sulfamic acid, and also organic acids, especially aliphatic, cycloaliphatic, aromatic aliphatic, aromatic or heterocyclic monobasics or poly Base carboxylic acid, sulfonic acid or sulfuric acid, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid Acids, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxysulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and -disulfonic acid, or laurylsulfuric acid can be used. For example, salts with physiologically unacceptable acids such as picrates can be used for the separation and / or purification of the compounds of formula (I).

Compounds of formula (I) and their physiologically acceptable acid-addition salts have been found to have useful pharmacological properties because they are well tolerated and especially act on the central nervous system. In particular, they inhibit 5-HT reuptake. In addition, this compound has great affinity for the 5-HT _x receptor (in 5-HT _x , where X is: 1A or 4), and has serotonin-acting and -antagonistic properties. Due to 5-HT-acting action and 5-HT reuptake inhibition, serotonin remains for a long time in the synaptic cleft, and serotonin action is enhanced. Thus, active ingredients having these properties are particularly suitable as antidepressants and anxiolytics. Compounds of formula (I) inhibit the binding of tritiated serotonin ligands to hippocampal receptors (Cossery et al., European J. Pharmacol. 140 (1987), 143-155) and inhibit synaptosome serotonin reuptake (Sherman et al., Life Sci. 23 (1978), 1863-1870).

In vitro confirmation of 5-HT reuptake inhibition (Wong et al., Neuropsycho-pharmacology. 8 (1993), 23-33) and p-chloroamphetamine antagonism (Fuller et al., J. Pharmacol.Exp. Ther, 212 (1980), 115-119). Inhibition of serotonin reuptake can also be investigated in vitro in the brain tissue of mice using the waldmeier method (European J. Pharmacol. 1977, 46, 387-92) or by microdialysis. And it is described in Dichiara, Trends in Pharmacol. Sci., 11 (1990), 116-121. For this reason, the physiological solution is perfused through the microdialysis vessel implanted in the rat brain. During this perfusion, the solution takes the neurotransmitter released into the brain and then dialysates. Thus, the 5-HT content in solution after perfusion is proportional to the amount liberated in the brain and increases, for example, after administration of 5-HT reuptake inhibitors (Gardier et al., Fundam. Clin. Pharmacol., 10 ( 1996), 16-27).

5-HT _1A -acting action is described in Matzen et al., J. Med. Chem., 43 (2000), 1149-57, in particular Eur. J. Pharmacol., 140 (1987), 143- As described on page 1156 of 155), it may be measured in vitro using, for example, a (serotonin) binding test. In addition, 5-HT _1A -agonistic action can be measured using the GTPgammaS test described in Newman-Tancredi et al. (Eur. J. Pharmacol. 307 (1996), 107-11).

In addition, changes in DOPA accumulation in striatum and 5-HT accumulation in N.raphe may occur after administration of a compound of formula (I) (Seyfried et al., Europ. J. Pharmacol. 160 (1989), 31- 41). In addition, analgesic and blood pressure lowering actions may occur. Thus, in conscious spontaneous hypertensive rats with catheter (see the methods of Weeks and Jones, Proc. Soc. Exptl. Biol. Med. 104 (1960), 646-648), blood pressure measured immediately after oral administration of the compound Falls. Thus, the compounds of formula (I) are also suitable for preventing and treating the consequences of cerebral infarction (cerebral hemorrhage) such as stroke and cerebral ischemia.

The present invention relates in particular to the use of compounds of formula (I) and their physiologically acceptable salts, derivatives, solvates and stereoisomers and mixtures thereof in all proportions as serotonin receptor ligands and / or for inhibition of serotonin reuptake. . In particular, the use of the compounds of formula (I) as 5-HT _1A agonists and as inhibitors of 5-HT reuptake is in accordance with the invention.

Accordingly, the present invention provides in particular compounds of formula (I) and / or physiologically acceptable salts, derivatives, solvates thereof for the manufacture of a medicament for the treatment of diseases, in particular diseases associated with serotonin receptors and / or serotonin reuptake. And the use of stereoisomers and mixtures of all proportions thereof.

The compounds of formula (I) according to the invention may be chiral due to their molecular structure and thus can take the form of various enantiomers. Therefore they may exist in racemic or optically active form.

Since the pharmaceutical efficacy of the racemates or stereoisomers of the compounds according to the invention may differ from one another, it may be desirable to use enantiomers. In this case, the final product or optionally even intermediates can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art or used as such in synthesis.

Since the compounds of the formula (I) have 5-HT _1A -acting properties while inhibiting serotonin reuptake, they are particularly suitable as antidepressants and anxiolytics.

Accordingly, the present invention also provides for the manufacture of medicaments such as anxiolytics, antidepressants, neuroleptics and / or anti-nausea medications, and / or OCD, sleep disorders, delayed dyskinesia, learning disorders, senile memory. Of the compounds of formula (I) and / or physiologically acceptable salts, derivatives, solvates and stereoisomers thereof, and all ratios thereof, for the beneficial action on disorders, bulimia or eating disorders such as IBS, and / or sexual dysfunction Relates to a mixture. Particularly preferred is the use for the preparation of a medicament as an antidepressant. The compounds of formula (I) can also be used as intermediates for the preparation of other pharmaceutical active ingredients.

Compounds of formula (I) are suitable for both animal and also human medicine to treat central nervous system dysfunction and inflammation.

The present invention thus relates to psychosis, schizophrenia, schizo-affective psychosis, cyclothymia, epilepsy, cramps, depression (sub-type severe depression and emotional circulation depression), Pathological anxiety (subtypes of panic attacks with or without plaque), excessive excitement, hyperactivity, stress illness, post-traumatic stress disorder, sleep disorders, lethargic seizures, periodic mood swings, attention disorders in children and adolescents, and mental retardation Severe developmental disorders and social behavior disorders, consultation (OCD) and widespread (OCSD) obsessive compulsive disorders, addiction disorders, malnutrition or eating disorders such as bulimia, obesity or anorexia, especially irritable bowel syndrome (IBS), fiber Psychiatric signs, impaired cognition (learning and memory disorders), especially senile memory disorders, dementia, delayed dysplasia of fibromylagia, and senile dementia and Alzheimer's form of dementia Kinesia, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Latism, Amyotrophic lateral sclerosis, Lewy body dementia, Tourette's syndrome, sexual dysfunction, premenstrual syndrome, acromegaly, hypogonadism, secondary Amenorrhea, unwanted puberty lactation, side effects of treating extrapyramidal motility disorders with conventional anti-Parkinson's medication to treat extrapyramidal motility disorders, and extrapyramidal symptoms (EPS), tension To treat the side effects of condition, neuroepileptic therapy induced by neuroleptics (e.g. using α-methyldopa), or for the prevention, treatment and control of cerebral infarction (cranial hemorrhage) such as stroke and cerebral ischemia. Or for the treatment of pain, especially chronic pain, migraine, CNS trauma, hypoglycemia, asthma, glaucoma, megacytosis, and other degenerative retinal diseases, incontinence, tinnitus Compounds of formula (I) and / or physiologically acceptable salts, derivatives, solvates and stereoisomers thereof, for the preparation of a medicament for treating hearing loss induced by an amino-glycoside antibiotic It relates to the use of a mixture of proportions.

However, they are particularly active as pharmaceutical active ingredients for anxiolytics, antidepressants, antipsychotics, neuroleptics, anti-nausea medications and / or obsessive-compulsive disorder (OCD), sleep disorders, delayed dyskinesia, learning disorders, senile memory disorders, eating It is suitable for acting favorably on disorders such as bulimia or IBS and / or sexual dysfunction.

The compounds of formula (I) are particularly usable for the preparation of pharmaceutical compositions by non-chemical methods. At this time, they are made into suitable dosage forms in combination with one or more solid, liquid and / or semi-liquid excipients or adjuvants and optionally with one or more additional active ingredient (s).

The present invention therefore also relates to pharmaceutical compositions comprising a mixture of at least one compound of formula (I) and / or physiologically acceptable salts, derivatives, solvates and stereoisomers thereof, and all proportions thereof. The invention also relates in particular to pharmaceutical compositions comprising additional excipients and / or adjuvants, and to pharmaceutical compositions comprising one or more additional pharmaceutical active ingredients.

The invention also specifically relates to compounds of formula (I) and / or physiologically acceptable salts, derivatives, solvates and stereoisomers thereof, and mixtures of all proportions thereof, with solid, liquid or semi-liquid excipients or auxiliaries Together and optionally with additional pharmaceutically active ingredients, to a suitable dosage form.

The pharmaceutical compositions according to the invention can be used as medicaments in human or veterinary medicine.

Suitable excipient materials include, for example, water, vegetable oils (such as sunflower seed oil or cod-liver oil), benzyl alcohol, polyethylene glycol, gelatin, carbohydrates (such as lactose or starch), magnesium stearate, talc, lanolin or petrolatum. , Organic or inorganic substances suitable for enteral (eg oral), parenteral or topical administration and which do not react with the novel compounds. Based on the expertise, those skilled in the art are well aware of adjuvants suitable for the desired pharmaceutical composition. Solvents such as, for example, water, physiological saline solutions or alcohols (such as ethanol, propanol or glycerol), sugar solutions (glucose or mannitol solutions), or mixtures of these solvents, gel formers, tablet aids and other active In addition to component excipients, for example, lubricants, stabilizers and / or wetting agents, emulsifiers, osmotic salts, antioxidants, dispersants, antifoams, buffers, flavors and / or aromatics or flavor enhancers, preservatives, solubilizers or dyes Can be used. If necessary, the composition or medicament according to the invention may comprise one or more further active ingredients, for example one or more vitamins.

The invention also

(a) an effective amount of a compound of formula (I) and / or physiologically acceptable salts, derivatives, solvates and stereoisomers thereof, and mixtures thereof in all proportions

(b) a set (kit) consisting of an individual pack of an effective amount of an additional pharmaceutical active ingredient.

This set includes a suitable container such as a box, individual bottle, bag or ampoule. This set includes, for example, an effective amount of a compound of formula (I), and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, mixtures of all proportions thereof, and effective amounts of additional pharmaceutical active ingredients, in which It can be made by including an individual ampoule each present in a predetermined form.

Tablets, dragees, capsules, syrups, juices, drops or suppositories are particularly suitable for enteral administration (oral or rectal), and solutions, preferably oily or aqueous solutions, also suspensions, emulsions or implants are parenteral Suitable for oral administration (subcutaneous or intravenous), ointments, creams, pastes, lotions, gels, sprays, blowing agents, aerosols, solutions (alcohols such as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, for example) , 1,2-propanediol or mixtures thereof and / or water) or powders are suitable for topical application. Liposomal compositions are also contemplated, in particular for topical applications.

The compound and / or its physiologically acceptable salts and solvates can also be lyophilized and the lyophilized product obtained can be used, for example, in the preparation of injectables. They can also be administered by nasal spray.

The compounds according to the invention can be administered to humans or animals, especially mammals such as apes, dogs, cats, rats or mice, and can be used for the treatment of the human or animal body and for the treatment of such diseases. They can also be used as diagnostics or reagents.

In the use of the compositions or medicaments according to the invention, the compounds and / or physiologically acceptable salts and solvates thereof according to the invention are generally analogous to known commercial compositions or preparations, preferably 0.1 to 500 mg per dosage unit. , In particular in dosages of 5 to 300 mg. The daily dosage is preferably 0.001 to 250 mg / kg, in particular 0.01 to 100 mg / kg by weight. The composition may be administered one or more times daily, for example twice, three or four times. However, individual dosages for each patient can be determined, for example, by the efficacy, age, weight, general health, sex, diet, time and method of administration, rate of excretion, combination with other agents, and the specifics of each compound used. It depends on a number of individual factors, such as the severity and duration of the disease. Oral administration is preferred.

The measure of absorption in an organism of a pharmaceutically active ingredient is its bioavailability. When a pharmaceutical active ingredient is supplied intravenously to an organism in the form of an infusion solution, its absolute bioavailability, ie the fraction of drug that reaches systemic blood (ie, the general circulation) is 100% in unchanged form.

In the case of oral administration of a therapeutically active ingredient, the active ingredient is generally in solid form in the composition and therefore is passed over the intestinal barrier, such as the gastrointestinal tract, oral mucosa, nasal mucosa, or skin (especially the stratum corneum) or is absorbed by the body. It must be dissolved first to make it possible. Pharmacokinetic data (ie on bioavailability) can be obtained similar to the methods of the literature (J. Shaffer et al, J. Pharm. Sciences, 88 (1999), 313-318).

Without further embodiments, it is contemplated that those skilled in the art will be able to use the above detailed description broadly. Accordingly, the preferred embodiments are to be considered in all respects only as illustrative and not restrictive.

Therefore, the following examples are intended to illustrate the invention without limitation. Unless stated otherwise, percentages refer to weight percent.

All temperatures are expressed in degrees Celsius. "Normal reaction finishing": add water if necessary, adjust pH to 2-10 if necessary according to the composition of the final product, extract the mixture with ethyl acetate or dichloromethane, separate the phases, and remove the organic phase Dry with sodium sulphate, filter, and evaporate, and residue is purified by chromatography and / or crystallization on silica gel.

Rf value on silica gel;

Mass spectroscopy (MS): EI (electron impact ionization) M ⁺

Fast Atomic Impact (FAB) (M + H) ⁺

THF (tetrahydrofuran), NMP (N-methylpyrrolidone), DMSO (dimethyl sulfoxide), EA (ethyl acetate), MeOH (methanol), TLC (thin layer chromatography)

The following materials were synthesized and characterized. However, this material can also be prepared and characterized by other methods by those skilled in the art.

Example  One:

Synthesis of 5- {4- [4- (5-cyano-1-methyl-1H-indol-3-yl) butyl] piperazin-1-yl} -benzofuran-2-carboxamide

a .: 0.8 g (20 mmol) of NaH is suspended in 20 ml of THF and 4.6 g (20 mmol) of 3- (4-chlorobutyl) -1H-indole-5-carbonitrile solution in 50 ml of THF is added dropwise at room temperature. do. The yellow solution is stirred for another 30 minutes, followed by the dropwise addition of 1.2 ml (20 mmol) of iodomethane solution in 30 ml of THF. The yellow solution is stirred at room temperature for 1 hour. The reaction solution is then evaporated and the residue is extracted by shaking with ethyl acetate and water. The organic phase is washed with water, dried using sodium sulfate and evaporated to give 5.4 g of oily residue which is crystallized with 15 ml of diethyl ether and 5 ml of petroleum ether, filtered off with suction and a small amount of di Wash with ethyl ether. Air drying gives 3.2 g of coarse pale-yellow crystals. [M + H ⁺ ] ESI-MS 457.

b. 540 mg (2.2 mmol) of indole obtained according to a. were suspended with 490 mg (2 mmol) of 5-piperazin-1-yl-benzofuran-2-carboxamide and 0.9 ml of triethylamine in 5 ml of NMP. Heat. The resulting solution is stirred twice at a bath temperature of 120 ° C. for 4 hours and cooled to room temperature over 10 hours. The reaction mixture is stirred in 100 ml of water. In the meantime, fine crystals precipitate. They are filtered off with suction, washed with water and dried in air overnight. The obtained 0.9 g of light brown crystals is finally chromatographed and purified to obtain 0.8 g of pale color crystals.

These are dissolved in hot acetone and 1 milliliter of ethanol HCl is added. White crystals precipitate immediately. They are again stirred at high temperature, suction filtered and washed with acetone.

Calculated Value C = 61.4 H = 5.9 N = 13.2 Cl = 13.4

Measured value C = 60.7 H = 6.0 N = 13.1 Cl = 12.7

Calculation based on dihydrochloride

Example  2:

Similarly to Example 1 the following products are prepared in particular:

Example  3: results of receptor binding test

Many of the compounds synthesized have nanomolar affinity for the 5-HT _1A receptor and nanomolar serotonin reuptake inhibition.

5- {4- [4- (5-cyano-1-methyl-1H-indol-3-yl) butyl] piperazin-1-yl} benzofuran-2-carboxamide (see Example 1)

SSRI 2.6 nmol / l (IC50)

5HT _1A 96nmol / l (IC50)

5HT ₄ 21 nmol / l (IC50)

Example  4: for injection Vials

A solution of 100 g of the compound of formula I and 5 g of dibasic sodium phosphate was adjusted to pH 6.5 with 2 N hydrochloric acid in 3 l of secondary distilled water, then sterile filtered, filled into an injection vial, lyophilized under sterile conditions and sterile Seal under conditions. Injectable vials containing 5 mg of the compound of formula (I) are obtained.

Example  5: Suppository

A mixture of 20 g of compound of formula I is melted together with 100 g of soya lecithin and 1400 g of cocoa butter, then poured into a mold and cooled. Suppositories containing 20 mg of the compound of formula (I) are obtained.

Example  6: Solution

A solution is prepared by dissolving 1 g of compound of formula I, 9.38 g of NaH ₂ PO ₄ .2H ₂ O, 28.48 g of Na ₂ HPO ₄ 12H ₂ 0 and 0.1 g of benzalkonium chloride in 940 mL of secondary distilled water. It is adjusted to pH 6.8, the solution is filled with 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.

Example  7: ointment

500 mg of the compound of formula I are mixed with 99.5 g of petrolatum under aseptic conditions.

Example  8: tablets

A tablet is prepared by compressing a mixture of 1 kg of a compound of formula (I), 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc, and 0.1 kg of magnesium stearate in a conventional manner such that each tablet contains 10 mg of the compound of formula (I).

Example  9: party

Similar to Example E, the tablets are compressed and then coated in a conventional manner using a coating of sucrose, potato starch, talc, tragacanth and dye.

Example  10: Capsule

A hard gelatine capsule is filled with 2 kg of the compound of formula (I) to prepare a capsule by a conventional method such that each capsule contains 20 mg of the compound of formula (I).

Example  11: ampoule

A solution of 1 kg of a compound of formula (I) dissolved in 60 l of secondary distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. An ampoule containing 10 mg of the compound of formula (I) is obtained.

Claims (14)

Compound of Formula (I): [Formula I]

(Wherein, X is N or CH, R ¹ , R ³ are independently of each other H, OH, OA, CN, Hal, COR ⁴ or CH ₂ R ⁴ , R ² is H, optionally mono- or poly-substituted by Hal, linear or branched alkyl having 1 to 6 carbon atoms, alkaryl, alkheteroaryl, or heteroaryl, R ⁴ is OH, OA, NH ₂ , NHB or NB ₂ , A and B are each independently alkyl having 1 to 6 carbon atoms, m is 2, 3, 4, 5 or 6, n is 0, 1, 2, 3 or 4) And physiologically acceptable salts, derivatives, solvates and stereoisomers thereof, and mixtures thereof in all ratios. The method of claim 1, X is N, R ¹ , R ³ are independently of each other CN, COR ⁴ or CH ₂ R ⁴ , R ² is linear or branched alkyl, alkaryl, alkheteroaryl or heteroaryl having 1 to 6 carbon atoms, R ⁴ is OH, NH ₂ , NHB or NB ₂ , A and B are each independently alkyl having 1 to 6 carbon atoms, m is 4, n is 0, And mixtures of physiologically acceptable salts, derivatives, solvates and stereoisomers thereof with all ratios thereof. The method according to claim 1 or 2, a. 5- {4- [4- (5-cyano-1-methyl-1H-indol-3-yl) butyl] piperazin-1-yl} benzo-furan-2-carboxamide b. 5- {4- [4- (5-cyano-1-ethyl-1H-indol-3-yl) butyl] piperazin-1-yl} benzo-furan-2-carboxamide c. 5- {4- [4- (5-cyano-1-isopropyl-1H-indol-3-yl) butyl] piperazin-1-yl} benzofuran-2-carboxamide d. 5- {4- [4- (1-benzyl-5-cyano-1H-indol-3-yl) butyl] piperazin-1-yl} benzofuran-2-carboxamide e. 5- {4- [4- (5-cyano-1-propyl-1H-indol-3-yl) butyl] piperazin-1-yl} benzofuran-2-carboxamide f. 5- {4- [4- (5-cyano-1-pyridin-2-ylmethyl-1H-indol-3-yl) butyl] piperazin-1-yl} benzofuran-2-carboxamide g. 5- {4- [4- (5-cyano-1-phenethyl-1H-indol-3-yl) butyl] piperazin-1-yl} benzofuran-2-carboxamide. a) a compound of formula II: [Formula II]

(Wherein, R ¹ and m have the meaning indicated in claim 1 and Y is halogen, in particular chlorine or an alcohol provided with protecting groups known to those skilled in the art) To the compound of formula III: [Formula III] R ² -Z (Wherein, R ² has the meaning indicated in claim 1, and Z is a leaving group known to those skilled in the art, for example p-tosyl, trifluoromethanesulfonyl, methanesulfonyl, benzenesulfonyl, Br, Cl or I Is reacted to), b) a compound of formula IV obtained according to a): [Formula IV]

Is a compound of Formula (V) or a salt thereof: [Formula V]

(Wherein, R ³ , X and n have the meanings indicated in claim 1) and optionally a base is added in the solvent to react at the boiling point of the solvent, c) a process for the preparation of a compound of formula I, characterized in that the base of the compound of formula I is converted to one of its salts by treatment with an acid. The method according to any one of claims 1 to 3, A compound according to any one of claims 1 to 3, as a serotonin receptor ligand and / or for inhibition of serotonin reuptake, and physiologically acceptable salts, derivatives, solvates and stereoisomers thereof, and all ratios thereof Mixture. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 3 and / or physiologically acceptable salts, derivatives, solvates and stereoisomers thereof, and mixtures thereof in all proportions. The method of claim 6, A pharmaceutical composition comprising additional excipients and / or adjuvants. At least one compound according to any one of claims 1 to 3 and / or physiologically acceptable salts, derivatives, solvates and stereoisomers thereof, mixtures in all proportions thereof, and at least one further pharmaceutical active ingredient Pharmaceutical composition comprising. A compound according to any one of claims 1 to 3 and / or physiologically acceptable salts, derivatives, solvates and stereoisomers thereof, and mixtures of all proportions thereof, as solid, liquid or semi-liquid excipients or auxiliaries Together with a suitable dosage form for the preparation of a pharmaceutical composition. Use of a compound according to any one of claims 1 to 3 and / or physiologically acceptable salts, derivatives, solvates and stereoisomers, and mixtures thereof in any ratio, for the manufacture of a medicament for the treatment of a disease. . A compound according to any one of claims 1 to 3 and / or physiologically acceptable salts, derivatives, solvates thereof for the manufacture of a medicament for the treatment of diseases associated with serotonin receptors and / or serotonin reuptake. And the use of stereoisomers and mixtures of all proportions thereof. For the manufacture of drugs such as anxiolytics, antidepressants, neuroleptics and / or anti-nausea medications, and / or obsessive-compulsive disorder (OCD), sleep disorders, delayed dyskinesia, learning disorders, senile memory disorders, macrophages or IBS A compound according to any one of claims 1 to 3 and / or physiologically acceptable salts, derivatives, solvates and stereoisomers thereof, for advantageously acting on such eating disorders and / or sexual dysfunctions, Use of mixtures in all proportions thereof. Psychosis, schizophrenia, schizo-affective psychosis, cyclothymia, epilepsy, cramps, depression (sub-type severe depression and emotional circulation depression), pathological anxiety (square Subtypes of panic attacks with or without phobias), excessive excitement, hyperactivity, stress illness, post-traumatic stress disorder, sleep disorders, narcolepsy, periodic mood swings, attention disorders in children and adolescents, severe developmental disorders including mental retardation, and Social behavior disorders, consultative (OCD) and broad (OCSD) obsessive compulsive disorder, addiction disorder, malnutrition or eating disorders, such as bulimia, obesity or anorexia, especially irritable bowel syndrome (IBS), fibromylagia, And psychiatric signs, cognitive impairment (learning and memory disorders), especially senile memory disorders, dementia, delayed dyskinesia, neurodegeneration Sexual disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Latirism, Amyotrophic lateral sclerosis, Lewy dementia, Tourette's syndrome, sexual dysfunction, premenstrual syndrome, acromegaly, hypogonadism, secondary amenorrhea, undesirable Unwanted adolescent lactation, side effects of treating extrapyramidal motility disorders with conventional anti-Parkinson's medication to treat extrapyramidal motility disorders, and extrapyramidal symptoms (EPS), tension, neuroleptics For the treatment of the side effects of hypertension therapy induced by (eg using α-methyldopa) or for the prevention, treatment and control of cerebral infarction (stroke), such as stroke and cerebral ischemia, or pain, in particular For the treatment of chronic pain, migraine, CNS trauma, hypoglycemia, asthma, glaucoma, megacytosis, and other degenerative retinal diseases, incontinence, tinnitus, or aminoglen A compound according to any one of claims 1 to 3 and / or physiologically acceptable salts, derivatives, solvates and steric forms for the preparation of a medicament for the treatment of hearing loss induced by lycoside antibiotics. Use of isomers and mixtures of all proportions thereof. a) a mixture according to any one of claims 1 to 3 and / or physiologically acceptable salts, derivatives, solvates and stereoisomers thereof, and mixtures of all proportions thereof, and b) A set (kit) consisting of individual packs of an effective amount of additional pharmaceutical active ingredient.